Many diseases that are mostly localized in a certain tissue are treated with systemically administered drugs. A well-known example of standard cancer therapy is a systemic chemotherapy coming along with significant side effects for the patient due to undesired biodistribution and toxicity. The therapeutic window of these drugs is usually defined by the minimal required therapeutic concentration in the diseased tissue on the one hand, and the toxic effects in non-targeted organs, e.g. liver, spleen, on the other. Localized treatment by, for example, local release of cytostatics from nanocarriers promises a more efficient treatment and a larger therapeutic window compared to standard therapeutics. Localized drug delivery is also important if other therapeutic options such as surgery are too risky as is often the case for liver cancers. Localized drug delivery can also become the preferred treatment option for many indications in cardiovascular disease (CVD), such as atherosclerosis in the coronary arteries.
Magnetic Resonance Imaging, usually based on 1H as the magnetic nucleus, is an important diagnostic technique that is commonly used in hospitals for the diagnosis of disease. MRI allows for the non-invasive imaging of soft tissue with a superb spatial resolution.
Magnetic Resonance Imaging based on 19F instead of 1H opens up new diagnostic possibilities. The 19F nucleus has a high gyromagnetic ratio (40 MHz/T) and a natural isotopic abundance ratio of 100%. In the human body, 19F containing structures are exclusively present in the form of solid salts in e.g. teeth and bones. As a consequence, the T2 relaxation times of the endogenous 19F atoms are extremely short and the MR signal is hardly detectable. In other words, the lack of endogenous 19F-based structures with relatively high transverse relaxation times assures a very low background MR signal. Therefore, exogenous 19F-based MRI contrast agents allow for “hot spot” imaging in a way similar to other techniques such as PET (positron emission tomography).
As a useful extension of its diagnostic use, MRI is also proposed for the monitoring of the delivery of bio-active agents such as therapeutic or diagnostic agents. I.e., MRI can not only be used for treatment planning, but also to control local drug delivery under image guidance.
In view of the aforementioned high specificity, it would be desired to employ 19F MRI not only as a diagnostic tool, but also in the MRI-assisted delivery of drugs or other biologically active agents. The same high specificity, however, also forms a practical barrier to the optimal use of 19F MRI herein. For, on the one hand, the addition of a 19F contrast agent to a drug carrier would mean that such a drug carrier were capable of being located by means of 19F MRI anytime, in view of the absence of natural 19F signal sources. On the other hand, it will mean that the detection of the 19F contrast agent does not provide information on the release of the biologically active agent, only on the presence of the contrast agent.
A reference respect of MRI monitored drug release is Ponce et al., J Natl Cancer Inst 2007; 99: 53-63. Herein a drug, doxorubicin, is taken up in a temperature-sensitive liposome. At body temperature, the doxorubicin remains in the inside of the liposome, whereas at a temperature of 41-42° C. the cytostatic drug is released from the inner aqueous compartment of the liposome. Thus, drug release can be facilitated by applying heat, as this will result in the opening-up of the liposome, whereupon drug release is no longer determined by diffusion (if any) through the liposomal shell. In order to monitor drug release by MRI, manganese is added to the formulation as an MRI contrast agent.
Almost all current MRI scans are based on the imaging of bulk water molecules, which are present at a very high concentration throughout the whole body in all tissues. If the contrast between different tissues is insufficient to obtain clinical information, MRI contrast agents (CAs), such as low molecular weight complexes of gadolinium, are administered. These paramagnetic complexes reduce the longitudinal (T1) and transverse relaxation times (T2) of the protons of water molecules. Also manganese acts as a T1 contrast agent.
The manganese contrast agent in the aforementioned drug carrier will act upon its exposure to the bulk water molecules detected by MRI, i.e. it will lead to instantaneous MRI contrast enhancement upon opening up of the liposomal shell above the melt transition temperature of the lipids, after the application of heat.
As described, the MRI used in this drug release process is in fact used to monitor the actual release, so as to confirm that the thermo-sensitive liposomes actually work. I.e., it merely provides ex post facto information.
It would be advantageous to use 19F MRI to guide and/or monitor the local release of a biologically active agent such as a drug. It would also be advantageous to monitor the fate of a drug carrier as of its administration. Also, rather than confirming, instantaneously, the fact that the drug is released, such monitoring is desired as to determine in advance if, when and where the drug release should take place. Particularly with thermo-sensitive drug carriers, it would be advantageous to localize the drug carrier, and apply the heat that serves to facilitate drug release on the spot where desired, and at the moment in time when desired. It is further desired to provide a monitoring possibility that does not necessarily vanish with the process of releasing a drug, and that can preferably be used to quantify the drug release process and to evaluate therapeutic efficacy.